University Of Florida

NIH Research Projects · FY 2025 · 2025-08

Project Summary & Abstract Advanced age is associated with compromised outcomes in differentiated thyroid cancer. This observation suggests that there is a biologic change due to aging that causes the poorer prognosis for the older adult. Studies of the aging thyroid have reported that detrimental immune modulation and cellular senescence contribute to thyroid diseases in the older adult, both of which have been implicated in the progression of malignancies. Aging is associated with a state of chronic inflammation due to the secretion of inflammatory proteins collectively known as the senescence-associated secretory phenotype (SASP) from senescent cells. There is a critical need to understand the connection between immune modulation and cellular senescence via the SASP and tumor progression in older adult patients. Our long-term goal is to better characterize the role of age-associated immune modulation in the development and progression of papillary thyroid carcinoma (PTC) in the older adult population. The overall objective of this proposed study is to elucidate the interplay of age and SASP production in thyroid tissue to guide personalized management of older adult patients with PTC. Our central hypothesis is that advanced age induces an SASP transcriptome in senescent thyroid fibroblasts that leads to enhanced progression of PTC. This hypothesis will be tested using publicly available large RNA sequencing datasets and single-cell RNA sequencing technology to pursue two specific aims: (1) to identify the contribution of advanced age to the SASP in thyroid tissue and (2) to identify alterations in the SASP transcriptome of aged thyroid fibroblasts due to local and locoregionally advanced PTC. This project is innovative because it is the first study to characterize the contribution of age to SASP production in normal thyroid tissue and leverage deconvolution techniques to isolate senescent thyroid fibroblasts of older adults to examine how the SASP contributes to PTC progression. The proposed research will establish validity for the unique SASP transcriptome in thyroid tissue and thyroid disease and lay the groundwork for further mechanistic studies into the role of older adult immune modulation in thyroid diseases.

NSF Awards · FY 2025 · 2025-08

This award will enable the development of advanced cyberinfrastructure to digitize and integrate over one million dragonfly and damselfly (Odonata) specimens from major natural history collections across the United States. The project, called Di-ODE (Digital Integration of Odonata), will create a unified, publicly accessible digital platform through Odonata Central, linking high-resolution specimen images with critical data such as collection localities and species identifications. This initiative will expand access to these important biological resources for scientists, educators, students, and the public. Di-ODE includes robust training programs to build skills in biodiversity data science and collections digitization. The project will enhance STEM education, promote data literacy, and engage community scientists, contributing to environmental awareness and scientific literacy. Through outreach and digital accessibility, Di-ODE will strengthen efforts to monitor environmental change and inform freshwater conservation across the globe. The project will transform how Odonata biodiversity data are accessed and analyzed by the research community. Dragonflies and damselflies are ecologically sensitive indicators of freshwater health and have been the focus of major studies in evolutionary biology, systematics, and biogeography. However, much of the valuable specimen data remains locked in poorly accessible physical collections. Di-ODE addresses this gap by creating efficient, scalable digitization workflows, using customized optical character recognition (OCR), advanced georeferencing, and data management tools. The resulting infrastructure will enable novel research in global change biology, comparative ecology, and phylogenetics. By improving data quality and access, Di-ODE will foster cross-disciplinary collaboration and provide a model for digitizing and mobilizing data from other invertebrate groups. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-08

Project Summary This project aims to advance phenotypic drug discovery (PDD) by developing a generative AI-driven platform for innovative, cell morphology-guided, scalable, and controllable small molecule design without relying on drug targets. By integrating tri-modal contrastive learning, controllable morphology generation, and retrieval- augmented molecule design, the platform addresses key PDD challenges, including limited understanding of structure–morphology relationships, inconclusive data generation, and lack of explainability in molecule design. Aim 1 will establish relationships among molecular structures, induced morphological changes, and textual descriptions to create a unified representation space. Aim 2 will develop a scalable and controllable diffusion model to generate morphology images that accurately reflect biological responses to chemical treatments. Aim 3 will implement a retrieval-augmented platform for traceable de novo small molecule design, leveraging external data sources to enhance explainability. This project will enable a target-agnostic approach to drug design, expanding therapeutic options for diseases without identified drug targets.

NIH Research Projects · FY 2025 · 2025-08

Modified Project Summary/Abstract Section ABSTRACT Each year, oral cavity and oropharyngeal cancers (OCC/OPC) claim the lives of over 12,000 Americans. Despite modest improvements in five-year survival rates, significant gaps remain in timely diagnosis and access to high-quality treatment. These gaps are especially prominent among individuals facing higher levels of socioeconomic risk, particularly black individuals, people with low incomes, as well as those residing in rural areas. Existing research has not fully characterized how the combined effects of individual and neighborhood-level social factors contribute to treatment and survival outcomes. Our central hypothesis is that multilevel social risk is a key driver of delayed treatment and increased mortality in OCC/OPC. This proposal will comprehensively evaluate upstream factors (economic stability, education access, healthcare access and quality, neighborhood-built environment, and social-community context) and use Artificial Intelligence (AI) and Machine Learning (ML) tools to develop and validate outcome-specific social risk scores to predict treatment and outcomes. We will use real-world electronic health record data from ~4,000 adult patients (aged 18 and older) diagnosed with OCC/OPC in the University of Florida Health System. These real-world data (RWD) will be linked with several external datasets (e.g., American Community Survey, Area Health Resources File) to evaluate outcomes, including treatment delay, receipt of guideline-concordant care, and mortality. We propose a study among patients diagnosed with primary OCC/OPC between 2012–2024. In Aim 1, we will build an RWD cohort of OCC/OPC and link multilevel datasets. In Aim 2, we will develop ML- based social risk management algorithms to predict OCC/OPC treatment and mortality. Findings will provide the foundation for scalable, patient-centered interventions that address social risk. Our future R01 will externally validate these risk scores, apply causal inference methods, collect patient-reported outcomes, and engage stakeholders to co-develop strategies for improving OCC/OPC care delivery and health outcomes across at-risk populations.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The variable clinical manifestations of SLE patients are largely unexplained. Although severe diffuse alveolar hemorrhage (DAH) with pulmonary capillaritis is unusual in lupus, more than half of patients with this complication die and focal lung hemorrhage occurs in 30-66% of patients. Using a mouse model (pristane-induced lupus) developed in our laboratory, we will ask why C57BL/6 (B6) mice are susceptible to pristane-induced DAH/vasculitis whereas BALB/c and DBA/2 mice are resistant. DAH is initiated by lung endothelial cell (EC) injury followed by recruitment of bone marrow-derived monocytes to the lung. We found that dysregulation of the extrinsic coagulation pathway also is involved and that lung disease is abolished by early treatment with MEK1/2 or ERK1/2 inhibitors. The overall hypothesis is that genetically- determined lung microvascular EC injury evolves into DAH because of monocyte infiltration into the lung and abnormal regulation of the extrinsic coagulation pathway. Aim 1 addresses susceptibility to DAH. We will ask whether EC injury and bleeding are lung-specific and investigate gene expression patterns associated with DAH by single-cell RNA-sequencing. Genes conferring susceptibility/resistance to EC injury and bleeding be mapped in recombinant inbred BXD (B6 X D2) mice. Aim 2 examines the MEK1/2-ERK1/2 pathway in pristane-induced DAH. We will define the sequence of events leading to DAH and develop blood-based diagnostic tests for the diagnosis of incipient DAH prior to the onset of bleeding. This is important, because the disease process is irreversible once hemorrhage begins. We will look for tests that distinguish early DAH (pre-bleeding) from other forms of lung injury, such as sepsis with acute respiratory distress syndrome. Aim 3 translates what is learned in mice to human DAH. We hypothesize that the disease process is similar except that the initial EC injury is caused by respiratory viral infections rather than pristane. We will ask if a predisposition to lung EC injury determines susceptibility, as in mice, and whether diagnostic approaches developed in the mouse model are relevant to human DAH. Lung EC injury will be examined in SLE patients with influenza or COVID infection and the role of mild bleeding disorders will be explored. The ability to diagnose incipient DAH (pre- bleeding) may permit future therapeutic trials using FDA-approved MEK1/2 inhibitors, such as trametinib, which are highly effective in pristane-induced DAH.

NIH Research Projects · FY 2025 · 2025-08

Abstract Despite effective antireroviral therapy (ART) suppression of HIV-1 replication to below the detection limit, latent proviruses can reinitiate viral production upon cell stimulation or treatment interruption. The HIV-1 Tat protein plays a pivotal role in regulating the transition between viral latency and active replication, enhancing transcript elongation from the HIV-1 promoter through a positive feedback mechanism. Tat inhibitors hold exceptional promise due to several reasons: 1) Tat is expressed early in the virus replication cycle; 2) No homologs of Tat exist in host cells; 3) Inhibition of Tat disrupts the essential positive transactivation feedback loop required for viral activation; 4) Disruption of this loop leads to epigenetic modifications at the HIV promoter, thus stably repressing viral reactivation. Tat also causes neurotoxicity and disrupts the blood-brain barrier causing neuroinflammation. Consequently, there is considerable interest in developing Tat inhibitors to complement ART. Furthermore, the block-and-lock HIV functional cure strategy relies on specific HIV transcriptional inhibitors to promote epigenetic silencing of proviral expression, locking the virus in a profound state of latency, from which reactivation is highly improbable post-ART interruption. This principle was demonstrated with the Tat inhibitor didehydro-Cortistatin A (dCA); however, clinical studies are pending due to dCA’s complex structure and costly synthesis. Therefore, additional structurally distinct candidates with equivalent bioactivity are essential in the pre-clinical pipeline. To discover novel Tat inhibitors with more cost-effective and simpler synthesis paths, we conducted a cell based high-throughput screening of several compound libraries. Using counter- screens and multiple orthogonal techniques to exclude non-specific and toxic molecules, we identified three small molecules with a therapeutic index (TI) greater than 10 and favorable chemical properties. Interestingly, all three compounds uniquely promote Tat protein degradation by activating the ubiquitin-proteasome pathway, effectively functioning as molecular glues. Here, we propose to carry out hit-to-lead validation and characterization, following a logical pathway for compound progression. The synthesis of novel analogs in each series, utilizing both traditional medicinal chemistry techniques and computational molecular dynamics, will be carried out by Dr. Bannister's medicinal chemistry group at UF Scripps. The structure-activity relationship (SAR) studies will be conducted collaboratively by the medicinal chemists and Dr. Valente’s virology group. Dr. Valente will evaluate the anti-HIV activity in human primary cells and conduct in depth characterization of the mechanism of action (MOA) of all the top-performing compounds. Additionally, ADME studies will be carried out by Dr. Cameron’s group at UF Scripps, and the antiviral efficacy of the compounds will be assessed using humanized mouse models of HIV infection in Dr. Garcia’s laboratory at the University of Alabama. At the conclusion of this study, we expect to have specific Tat inhibitors/degraders with good metabolic and pharmacokinetic properties that prove highly effective in reducing HIV transcription in studies involving humanized mice.

NIH Research Projects · FY 2025 · 2025-08

SUMMARY Membrane proteins and lipids are organized into signaling domains in the cell membrane that are hundreds of nanometers in size. These signaling domains are essential for the efficiency and specificity required for cell signaling. The long-term vision of my research program is to determine the molecular compositions and structures of these membrane protein signaling complexes and understand how their organization results in their physiological function. This overall vision will be fulfilled through two independent tasks. One is to determine the molecular mechanisms underlying individual components in a signaling pathway. The other is to directly study the complex as a whole to understand how different components are assembled with each other. In the next five years, my goal is to exercise these two tasks on a specific membrane protein ─ the TRPM3 ion channel. TRPM3 plays a critical role in nociceptor neurons and mediates inflammatory hyperalgesia and pain sensation. The activity of TRPM3 is tightly regulated by the G protein-coupled receptor (GPCR) signaling pathway. Specifically, we will determine the structures and activities of individual TRPM3 channels in isolation and in cell membranes to understand the molecular details governing its transition between closed, open, and desensitized states. We will also determine the compositions and structures of the TRPM3 signaling complex in the cell membrane to understand how the organization of lipid and protein molecules contributes to TRPM3 signaling efficacy. We will use electrophysiological recordings in cells and in reconstituted membranes to isolate the contributions from individual protein and lipid partners. The results from this proposal will not only advance our molecular understanding of the TRPM3 function but also contribute to the emerging field of integrative structural biology, where we study the structure of signaling complexes in the native environment using a multitude of atomistic and molecular approaches. Our efforts will also lead to the development of new methods to study TRPM3 ion channels in their native environments that are broadly applicable to other membrane proteins and signaling pathways.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Despite significant progress in HIV testing and vertical transmission prevention programs, over 100,000 children are still infected annually, predominantly in sub-Saharan Africa. Several factors contribute to this high burden of pediatric HIV infections in the region, including inadequate healthcare infrastructure, limited access to clinics, maternal infections during pregnancy, and stigma. Additionally, high rates of unplanned pregnancies among women living with HIV, many of whom struggle with antiretroviral therapy adherence, complicate efforts to eliminate pediatric HIV. While breastfeeding is a major route of vertical HIV transmission, it is also a pillar of child survival in Africa, so a key challenge in developing pediatric HIV interventions is ensuring safer breastfeeding for at-risk infants in a way that is practical, discreet, and does not require strict adherence to treatment. Passive immunization with broadly neutralizing antibodies (bNAbs) offers promise for preventing pediatric HIV infections. However, the current approach, which relies on repeated infusions of recombinant bNAb proteins, is both expensive and difficult to implement in resource-limited settings. A potentially transformative alternative is adeno-associated virus (AAV)-mediated gene transfer, which enables continuous in vivo production of bNAbs by host cells, thereby eliminating the need for repeated dosing. This strategy is particularly attractive due to the excellent safety profile of AAV vectors and their ability to transduce long-lived cells, such as myocytes, allowing for durable bNAb expression. Consistent with the phenomenon of neonatal tolerance, we recently identified the first four weeks after birth as an optimal window for achieving high and sustained bNAb expression in infant rhesus macaques (RhMs) following AAV/bNAb therapy. Beyond this period, the effectiveness of the therapy diminishes significantly as infants develop the ability to mount humoral immune responses against the AAV-delivered bNAb (also known as anti-drug antibodies, or ADAs) that reduce or shut down transgene expression. To extend the 4-week window for effective AAV/bNAb therapy, we sought ways to prevent ADAs in infants treated beyond the neonatal stage. We discovered that RhMs exposed in utero to a recombinant form of the same bNAb delivered by AAV did not mount ADAs after postnatal AAV/bNAb treatment, even when the vector was given at 3 months of age. However, this effect waned by 8 months, at which point treatment outcomes became indistinguishable between prenatally exposed and bNAb-naïve RhMs. Thus, the immunological program responsible for prenatally induced tolerance to the AAV-delivered bNAb appears to be “switched off” at some point between 3 and 8 months of age. Based on these data, this project seeks to elucidate the mechanism of in utero bNAb tolerization in primates (Aim 1) and prolong bNAb tolerance throughout infancy (Aim 2). Ultimately, our goal is for a one-time administration of AAV/bNAb vectors to generate long-lasting (possibly lifelong) HIV immunity in children of all ages.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Freezing of gait (FoG) is a common symptom in Parkinson’s disease (PD), characterized by a sudden reduction in forward stepping movement, leading to falls and reduced quality of life. The combination of FoG and difficulties in adapting walking patterns to different situations further increases the risk of falls in PD, highlighting a critical need for improved understanding and strategies to alleviate these gait impairments. This project aims to understand the neural mechanisms underlying locomotor adaptation deficits in PD with FoG. We will study neural activity in the globus pallidus internus (GPi), the major basal ganglia output center, using novel deep brain stimulation (DBS) technology with recording capabilities during treadmill walking in PD. We posit that abnormal neural oscillations in the GPi disrupts the regulation of human walking, and we hypothesize that an increase in 13-30 Hz oscillatory activity may lead to locomotor adaptation deficits in PD with FoG. The proposed studies will include 60 PD patients implanted with GPi-DBS, 20 of whom will have the Medtronic Percept PC capable of recording local field potential (LFPs). Locomotor adaptation will be studied using a split-belt treadmill paradigm, consisting of baseline (1:1 speed ratio), split-belt adaptation (2:1) and post-adaptation (1:1) walking. The experiments will be performed under DBS ON and DBS OFF conditions. We will capture joint kinematics and electromyography (EMG) to characterize locomotor adaptation deficits and various types of FoG manifestation. GPi LFP recordings will be aligned with motion capture and EMG data. Aim 1 will identify GPi LFP oscillations related to locomotor adaptation deficits and FoG in PD. Aim 2 will determine whether GPi-DBS facilitates split- belt walking adaptation in PD. This work has theoretical and translational significance because the outcomes will provide new scientific knowledge regarding the role of pallidal neural activity in human walking adaptation, and identify new strategies to mitigate locomotor adaptation deficits associated with FoG in PD.

NIH Research Projects · FY 2025 · 2025-08

Project Summary and Abstract In the field of nanomedicine, there are several challenges: (1) the delivery efficiency of nanoparticles (NPs) to tumor is very low (<1% injected dose); (2) it is unknown whether there is a sex difference in tumor delivery efficiency of NPs; (3) there is a lack of models that can predict distribution of NPs and the carried drug to tumor and major organs and extrapolate from animals to humans. To address these challenges, the objective of this renewal application is to develop a mechanistic, well-validated, and predictive generic physiologically based pharmacokinetic (PBPK) models for NPs and the carried drug in male and female tumor-bearing mice that is extrapolatable to rats. We hypothesize that tissue distribution and tumor delivery of NPs and the carried drug can be predicted with a well-trained PBPK model by using species-specific, sex-specific, and NP-specific parameters with machine learning and artificial intelligence (AI) approaches. Compared to the previous cycle of this R01 grant, this renewal is innovative in several aspects: (1) the first time to systemically analyze whether there is a sex difference in tumor delivery efficiency of NPs; (2) the first PBPK model for NPs in tumor-bearing animals to evaluate the cross-species extrapolation capability, which is critical to extrapolate animal results to humans; (3) the previous cycle of this grant only focused on NPs in tumor using a single-task learning model, but this renewal will comprehensively analyze distribution of NPs and the carried drug to both tumor and major organs using multi-task learning models. Three specific aims were designed. Aim 1: To develop a PBPK model for NPs and its carried drug in male and female tumor-bearing mice using traditional PBPK approaches. Aim 2: To develop a robust, validated and predictive AI-assisted generic PBPK model for NPs and its carried drug in male and female tumor-bearing mice by employing machine learning and AI approaches. Aim 3: To validate our PBPK model with new experimental data, extrapolate it to rats, and convert it to an AI-empowered web dashboard. In Aim 1, we will create a Nano-Drug Database by including new data published from 2021-2029, especially new data on the carried drugs of NPs, which were not included in previous studies. In Aim 2, the multi-task machine learning model enables to determine the impact of distribution to major organs on tumor delivery efficiency. In Aim 3, we will conduct original pharmacokinetic and tissue distribution experiments in both tumor-bearing mice and rats to evaluate and validate our model. This project is significant because it directly addresses the low tumor delivery efficiency of NPs, which is a critical barrier to progress in this field for >2 decades. This project has broad impacts because this project will create tangible nanomedicine database and AI-empowered PBPK model to answer a key question on the potential sex difference, improve our scientific knowledge on key determinants of tumor delivery efficiency of NPs, and provide a high- throughput screening tool to improve our technical ability to efficiently screen and design new nanomedicines, and help reduce animal experimentation and ultimately accelerate clinical translation of nanomedicines.

NSF Awards · FY 2025 · 2025-08

CAREER: The Aligning Learners' Intentions with Goals and Needs (ALIGN) Model: Connecting Learners to STEM Careers Through STEM Micro-credentials The Faculty Early Career Development (CAREER) program is a National Science Foundation-wide initiative that supports early-career faculty in advancing research and education. The U.S. STEM workforce plays a critical role in driving innovation and economic growth, yet many individuals seeking careers in STEM face challenges due to unclear pathways between education and employment. STEM micro-credentials provide targeted, competency-driven training that offers flexible, efficient alternatives to traditional degrees, making them a powerful tool for strengthening the STEM talent pipeline. However, broader adoption is hindered by unclear quality standards, inconsistent alignment with workforce needs, and limited transparency in credential-to-career connections. This CAREER project lays the foundation for improving the alignment between STEM micro-credentials and career pathways, helping learners make more informed decisions about their education and professional development. By advancing research-based strategies to enhance the credibility, usability, and transparency of STEM micro-credentials, this project will contribute to stronger connections between education, industry, and workforce needs. This research employs a four-phase approach to examine how learners make career-related decisions and engage with STEM micro-credentials. The project will validate an instrument to assess hurdles, enablers, and motivators influencing learners, generating insights that contribute to lifelong learning and workforce integration. Findings will inform the development of learner personas—data-driven archetypes designed to connect learners’ decisions and needs with career pathways—providing a structured approach to understanding how micro-credentials better support workforce transitions. Additionally, the project will establish an open-access repository that maps micro-credential pathways to STEM careers, fostering higher education-industry collaboration and improving credential transparency. These efforts will provide a research-backed foundation for enhancing the role of STEM micro-credentials in workforce development. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT The integrity of the visual system during infancy has been associated with later developmental and cognitive outcomes, suggesting that visuocortical function plays a foundational role for cognitive development. However, the development of the visual system is complex, and it is unlikely that a single measure reliably predicts cognitive function. The proposed research will assess the development and predictive value of infant visual function using a battery of tasks and machine learning techniques in a longitudinal sample of infants tested at 6-, 10-, 14- and 18- months of age. A vision screener and electrophysiological measures will be examined in relation to concurrent and subsequent cognitive performance measured by the NIH Infant and Toddler (Baby) Toolbox (NBT). Aim 1 of the proposed work is to characterize infant visuocortical function and developmental trajectories using a battery of tasks that measure (1) Visual Evoked Potentials (VEP), (2) frequency-tagged steady state Visual Evoked Potential (ssVEP), (3) occipitotemporal oscillatory EEG activity (dominant rhythm (alpha oscillation), (4) Event-related potentials (ERPs) in response to faces and objects, (5) refractive errors and ocular misalignments associated with poor vision using the Welch Allyn Spot Vision Screener, and (6) the development of pupil size, pupil distance, and eye gaze deviations. Models of development will be examined for each measure to estimate trajectories of developmental change as well as the internal consistency and trial by trial reliability of the EEG measures using Bayesian Hierarchical Linear Models (BHLM). Aim 2 is to determine the extent to which reliable indices of visuocortical function predict concurrent and later developmental outcomes using two different innovative data integration models. To address Aim 2, visual processing measures (VEP, ssVEP, EEG, ERP, and metrics from the Spot Vision Screener) will be used as predictors in statistical models that link them to concurrent and future results from the NBT (Cognition, Executive Function, Language, Numeracy, Self-Regulation, Habituation, and Reaction time). A combination of the BHLM methods and Variational Autoencoders will be used to reduce the data into a subset of reliable predictors. The short-term goal of the proposed work is to delineate the developmental trajectory of visuocortical function across infancy and determine the predictive value of a battery of visual measures in relation to concurrent and later cognitive processes. The long-term goal of the proposed work is to establish a reliable and informative index of healthy visual development that captures developmental complexity and can be widely applied in the future.

NIH Research Projects · FY 2026 · 2025-08

Project Summary RNA localization and local translation are vital for cellular function and adaptability. These processes confer several advantages, such as enabling proteins to be synthesized precisely when and where they are needed, reducing the reliance on protein transport, protecting RNAs from degradation, and optimizing the cell's energy use. By coordinating RNA stability, transport, and translation within specific subcellular regions, local RNA regulation allows for rapid cellular responses to external cues. This is especially important in processes like homeostasis, differentiation, migration, immune responses, and synaptic plasticity. However, despite these advantages, several key aspects of RNA localization and local translation remain poorly understood. We lack a complete understanding of the molecular triggers, conditions, and mechanisms that determine where and when RNAs are translated or how these processes mediate cellular adaptation. For instance, it is unclear how cells prioritize which RNAs to translate in response to specific stimuli or how different subcellular regions synchronize these responses. Local organelle regulation and the timing and regulation of localized translation, especially in relation to upstream open reading frames (uORFs) and RNA-binding proteins (RBPs), also remain a mystery. These gaps in knowledge limit our understanding of how cells adapt to stress or adjust to physiological demands. The proposed research in this application aims to address these knowledge gaps using neurons as a model system. By leveraging advanced imaging tools and innovative TurboID-mediated proximity labeling approaches, applied both in vivo and in vitro, this research will illuminate how local RNA regulation influences mitochondrial function under dynamic cellular demands. Additionally, it will examine how the local molecular machinery shapes cellular responses and how these mechanisms are conserved or diverge across different species, shedding light on the evolutionary conservation of these processes. The emphasis will particularly be on identifying this regulation in response to adaptive stimuli. Comparing adaptive responses across different cell types and species will also offer crucial insights into how shared and divergent mechanisms determine cellular and organismal fitness and how disease susceptibility arises. This research application targets foundational questions in cellular biology and pathology, focusing on RNA-centric mechanisms that play critical roles in neuronal communication and influence the entire organism. By advancing our understanding of how subcellular RNA regulation and protein synthesis occur at neuronal junctions, this work aims to provide valuable insights relevant not only to neuroscience but to general medicine. The findings from this study could pave the way for new therapeutic approaches that extend beyond neurological disorders, addressing broader cellular and metabolic conditions. This interdisciplinary approach promises to push the boundaries of RNA biology, offering potential innovations that could benefit a wide range of medical fields.

NSF Awards · FY 2025 · 2025-08

PUBLIC ABSTRACT This project will reveal how venom complexity has evolved in association with sociality in spiders. The evolution of sociality is associated with a redistribution of efforts among group-mates to accomplish collective tasks. However, how social groups of predators optimize the distribution of weaponry used to subdue prey remains unknown. Venomous predatory spiders represent a powerful system to address this gap in knowledge because both social and solitary spiders use venom for defense and prey capture. This project explores how venom – a critical tool for defense and hunting – is shaped not only by an animal’s biology, but also by the microbes (the “microbiome”) that live within it. Researchers will study how venom composition, including both toxins and microbial communities, has changed across multiple independent origins of social living in spiders. By comparing venom traits in social spiders and their solitary relatives, the team will examine whether social living drives changes in venom that help divide labor among individuals. This work is significant because it brings together tools from evolutionary biology, toxinology, and microbiome science to ask how cooperation in nature evolves, and if this evolution is repeatable. It also has real-world relevance in that spider venom and venom microbes may hold clues for developing new natural products or medicines, including treatments for chronic pain and infections. The researchers will share their discoveries, as well as educational resources for inspiring students to apply the scientific method to both basic and applied research questions, with students from local communities in both Florida and Puerto Rico. This research investigates how venom complexity – defined here as the combined diversity of venom toxins and venom-associated microbial communities – has evolved in association with three independent origins of sociality in spiders. Using complementary multi-omics techniques, the research team will quantify two components of venom composition, toxin diversity and venom microbial community diversity, to assess within- and between-species differences in venom complexity. Three research objectives will be addressed: the team will (1) determine differences in venom toxin composition between social and solitary predators, (2) identify differences in venom microbiomes between social and solitary predators, and (3) establish the degree to which individual venom composition coincides with behavioral task differentiation. This proposal expands the traditional view of venom evolution to encompass the functional role of venom-associated microbes across multiple scales: from individuals to social groups to populations to species. Using Stegodyphus social spiders as a test system allows us to address the parallel evolution of two key innovations (sociality and venom use) across multiple origins of sociality. Few systems exist in which these key innovations are genetically tractable, allowing for the mapping of precise mutational pathways and revealing underlying microevolutionary processes. From a biotechnology perspective, venom peptides provide a large untapped potential for therapeutic discoveries, including treatments for chronic pain and parasite infection. Characterization of the venom microbiome has high potential to yield novel taxa of biomedical importance because this microbial community inhabits venom-gland environments known for their antimicrobial properties. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Unveiling the brain-muscle axis associated with aging could be a key to many diseases, including Alzheimer's disease (AD) and Parkinson’s disease (PD) prevention and rehabilitation. Several modes of communication between the brain and muscle have been explored in the research field, including the emerging route via circulating extracellular vesicles (EVs). Elucidating an EV-enabled communication network between the brain and skeletal muscle could reveal essential molecular targets and signaling pathways, resulting in more effective therapeutic strategies to prevent brain aging and expand health span. We hypothesize that vital molecular drivers indicating the effects of microgravity on human brain-muscle physiology could be revealed to correlate with age-associated conditions. In UG3 PHASE (Year 1-Year 2), we will focus on the on-ground development of brain-muscle MPS to be used in microgravity environments. We will Integrate with the flight hardware provided by implementation partner for payload, functioning in an automatic regime, and recapitulating key features of brain-muscle physiology to achieve initial flight testing. In UH3 PHASE (Year 3-Year 5), we seek to understand microgravity effects and regenerative EVs on human brain-muscle physiology to correlate with age-associated conditions for therapeutic development. We will integrate the second space flight testing to achieve anti-apoptotic and regenerative potency assessment for therapeutic development using regenerative EVs. Our long-term goal is to establish space enabling brain-muscle MPS to understand brain-muscle physiology in space and develop EVs as a practical therapy approach to prevent aging.

NIH Research Projects · FY 2024 · 2025-08

Project Summary / Abstract Alcohol use disorders (AUDs) are associated with neurodegeneration and cognitive dysfunction, but the impact of alcohol use on Alzheimer's disease and related dementias (ADRD) is unknown. Our work suggests that chronic alcohol can alter the activity of serotonin (5-HT) neurons in the DRN, which may cause disruption in sleep homeostasis in the early stages of ADRD. Both AUD and ADRD are associated with chronic insomnia, but to date no studies have linked alcohol-induced sleep disturbances to tau-based neuropathology in the brain. Sleep disruption also induces microglial activation and aging, which can promote the spread of tau pathology in the brain. In Aim 1, we will use EEG, fiber photometry, electrophysiology and DREADD-based manipulations of neural activity in vivo in mice expressing human tau pathology (htau mice) to determine whether chronic alcohol exacerbates sleep deficits and whether enhanced neural activity in 5-HT neurons contributes to sleep disruptions. In Aim 2, we will examine the effect of chronic alcohol on microglia and their contribution to the progression of tau pathology in the DRN. In Aim 3, we will determine whether chronic alcohol can facilitate the spread of tau pathology from the DRN to other brain regions using an AAV-based strategy for expressing tau pathology exclusively in 5-HT neurons. 3D immunolabeling and light sheet imaging using the iDISCO technique will be used to identify areas and quantify the extent of tau spread. We will also examine whether neural activity in 5-HT neurons and microglial activation contributes to this spread. In total, the proposed research will provide mechanistic insight into the impact of chronic alcohol on early accumulation and spread of tau pathology in the brain and the later development of cognitive and memory deficits.

NSF Awards · FY 2025 · 2025-08

This Faculty Early Career Development (CAREER) grant will fund research that enables soft-bodied unmanned underwater vehicles that use the soft body itself for control, thereby promoting the progress of science, advancing the national prosperity and welfare, and securing the national defense. Unmanned underwater vehicles could become vital devices for monitoring the constantly changing coastal environment, supporting critical infrastructure at the bottom of the ocean, and defending our nation. However, existing underwater vehicles face challenges when operating in coastal waves and currents and under crushing pressures at the ocean’s depths. In contrast, fish can freely swim from the coast to the abyss by leveraging their soft body for high maneuverability, quiet swimming, and efficient deep-water operation. Robotic vehicles with soft bodies aim to harness these biological benefits; however, controlling these soft vehicles is a significant challenge. This project will attempt to solve this challenge by enabling soft robotic fish that harness the swimming benefits of biology and require minimal computing resources. To accelerate the use of biologically-inspired underwater vehicles and inspire an educated workforce, this project will integrate outreach and education into the research. This project will conduct outreach to coastal scientists to identify use-cases and requirements for bio-inspired underwater vehicles, will develop soft robot learning kits to spark scientific curiosity in 4th grade students, and will provide undergraduate research opportunities. This project aims to establish a fundamental framework to control undulatory soft robotic swimmers using the embodied intelligence of the swimmer’s own physical dynamics. It will achieve this goal using physical reservoir computing, which will turn a swimmer’s nonlinear fluid-structural dynamics into a physical embodiment of a neural network and use this embodied intelligence to control the undulatory gait. This project will combine physical soft robots with computational models to identify the relationship between the embodied undulatory gait and the swimming performance as a function of the body dynamics, muscle actuation, sensory feedback, and active body stiffness. This research involves three key objectives: 1) identify the fundamental relationships governing control of the muscles and undulatory gait using embodied intelligence, 2) determine the relationship between active body stiffness and embodied control, and 3) harness the identified relationships to control the soft robot across swimming conditions. Fundamental relationships that could be uncovered in this project will generalize to advance the control of soft robots using physical reservoir computing and will extend beyond the boundaries of control, morphology, artificial muscle, and sensor type. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-08

Abstract The oral epithelium is often the gateway for many different viruses into the human body. The oral cavity has a complex multi-species microbiome, which includes bacteria, fungi, and viruses. The interaction between the different microbiome elements and the bacterial secretions such as short-chain fatty acids (SCFAs) play a crucial role in regulating oral infections, however, the underlying mechanisms are still largely unknown. Clinical studies on periodontitis showed that the amount of oral bacteria (e.g., P. gingivalis) correlates with that of herpesviruses including the human oncogenic DNA virus, Kaposi's sarcoma-associated herpesvirus (KSHV). The primary route of KSHV infection in humans is through the oral cavity, which is the least understood step in KSHV infection. The goal of our study is to determine the molecular mechanisms that control the infection of oral epithelial cells by KSHV and how oral KSHV infection is affected by oral bacteria and their metabolites such as SCFAs. We found that P. gingivalis and bacterial metabolites can increase the expression of stress response-related cellular transcription factors in oral epithelial cells, and they are crucial for the robust herpesvirus infection of oral epithelial cells. Based on our preliminary data, we hypothesize that the reason that the oral epithelial cells are supportive of lytic KSHV infection is because they have unique cellular properties, which SCFAs can upregulate resulting in enhanced KSHV infection. In Aim 1 of this proposal, we will investigate the mechanism by which SCFA increases the protein level of stress response-related host transcription factors in oral epithelial cells and how they promote KSHV infection. Aim 2 will focus on the identification of KSHV factors that can also induce stress response-related host transcription factors, and their importance in the KSHV infection of oral epithelial cells will be investigated. We envision that understanding of how the metabolites of oral bacteria support KSHV infection in the oral epithelium will help to find targets that can be used for developing new therapeutic antivirals to block oral infection not only by the cancer-causing virus KSHV but potentially by other human pathogens as well.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Swallowing is a complex motor behavior that relies on rapid, precise coordination between the respiratory and swallowing pathways to protect the airway. Even minor disruptions in this coordination can result in dysphagia, which significantly increases the risk of aspiration pneumonia—a leading cause of death among individuals with neurological disorders. Dysphagia is especially concerning in those with spinal cord injury (SCI), where pneumonia is responsible for 65% of deaths in individuals with high cervical injuries (C1-C4). While dysphagia is often considered a transient issue following acute SCI, emerging evidence from both animal and human studies suggests it may persist into the chronic phase, potentially contributing to silent aspiration and elevated morbidity. The fundamental goal of this project is to redefine our understanding of dysphagia following SCI by investigating the progression and underlying mechanisms of upper airway dysfunction in SCI. Specifically, we aim to characterize the development and extent of upper airway dysfunction from acute to chronic phases of cervical SCI using a clinically relevant rodent model of SCI (C4 contusion). Through this model, we will evaluate how changes in the neurochemical profile of upper airway motor neurons may underpin the persistence of dysfunction over time. Additionally, we will explore the mechanisms by which chronic SCI contributes to functional swallowing impairments and aspiration, which seem to differ from those observed in the acute injury phase. Utilizing a well-established C4 contusion model of SCI, we will assess time-dependent changes in swallow function and neural circuit reorganization. This research will lay essential groundwork for future studies aimed at identifying therapeutic targets to mitigate dysphagia and improve respiratory outcomes for individuals with chronic SCI. Moreover, our findings may have broader implications for other neurological conditions with high dysphagia and aspiration rates, including traumatic brain injury and stroke.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY In public health sciences, people’s accessibility to healthcare determines how easily they can reach and utilize health services. For researchers and policy makers, modeling and measuring accessibility to healthcare is key to narrowing disparities and achieving health equality. Each year, a plethora of research efforts aim to model, estimate, and map geographic disparities in healthcare accessibility, informing targeted interventions in underserved areas. These studies have predominantly adopted either a travel cost-based approach or supply- demand approach to measure accessibility. Both approaches are population-based and temporally static, assuming uniformity among individuals and disregarding temporal factors. The derived accessibility measures fail to account for temporal variations, as well as heterogenous individuals and their interactions. To address these limitations, I will propose new conceptual frameworks to model and validate accessibility to healthcare using a system science approach. This two-year small project will study people’s access to healthcare in a dynamic and social system that involves complex interactions among individuals, as well as interactions between individuals and the environment (e.g., transportation network and health facilities). I will pioneer two models in system science, namely the system dynamics model and the agent-based model, to represent this system. I will implement these two types of models in the state of Florida in the context of recent ‘triplepidemic’ (flu, RSV and COVID) during 2022-23 season, and attempt to validate the model results. This study will contribute to the literature by adding a time dimension, individuals’ heterogeneity, and their social networks to the models of healthcare accessibility. Additionally, this study will investigate a novel method to validate healthcare accessibility models, addressing a persistent gap in existing research. Researchers and policy makers can use the newly developed tools to better monitor dynamics of healthcare accessibility and to mitigate health disparities more precisely with spatio-temporally dependent intervention.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT Bacterial pathogens employ a myriad of mechanisms to invade the host, evade immune responses and inflict damage. Arguably the most pathogenic bacterium known is Francisella tularensis, which boasts a mortality rate upwards of 60%, is transmitted via aerosols, and can be made antibiotic resistant through rudimentary methods. Based on these characteristics, F. tularensis is one of only three bacteria of highest concern for weaponization by the Centers for Disease Control and Prevention. Although these bacteria have been studied since the early 1900s, we still lack a protective and non-toxic vaccine. These intracellular bacterial pathogens employ a contractile toxin secretion apparatus called the type VI secretion system (T6SS) to inject effector proteins into host cells to facilitate invasion into the cytosol and proliferation. Deleting any component of the T6SS apparatus or the effector proteins that it secretes renders Francisella avirulent. In this application, we propose to use an established antigen delivery strain of Salmonella to insert Francisella T6SS proteins directly into phagocytic cells to induce protective immunity. The protective immunity enhanced Salmonella vaccines (PIESVs) are composed of S. Typhmurium strains that simultaneously induce antigen expression and self-destruct within 8-10 cell divisions in the host. This results in antigen delivery into phagocytic cells within lymphoid tissue and has been used extensively as an antigen delivery platform. We will construct PIESV strains that express T6SS proteins and determine if they can elicit protective immunity in a mouse model for Francisella infection. These studies will provide insight into antigens that are protective against subsequent infection.

NIH Research Projects · FY 2025 · 2025-07

Abstract Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus that is the etiological agent of several AIDS-related malignancies such as B cell lymphomas and Kaposi's sarcoma. KSHV establishes viral latency in most cell types following primary infection but can undergo lytic reactivation. The key viral factor, which drives the lytic cycle of KSHV, is the replication and transcription activator called RTA. We and others have identified the genome-wide targets of RTA and we have also demonstrated the need for the rapid induction of specific host genes concomitantly with the viral genes for efficient lytic reactivation. Uncovering the protein interaction domains of host factors that viral proteins bind to and are crucial for lytic reactivation is important, because they can serve as potential targets for antiviral therapies to abrogate viral transmissions. Our study focuses on one such domain of host factors called the Forkhead-associated (FHA) domain. This is a unique protein-protein interaction domain, which recognizes and binds to specific conserved short linear motifs in proteins. FHA proteins have diverse functions in the regulation of transcription, DNA repair, replication stress response and cell cycle checkpoints. Viral proteins often mimic host protein interaction motifs thereby hijacking host factors and alter cellular functions. Through our unbiased in silico protein sequence screening of KSHV proteins, we identified several viral proteins possessing putative FHA interaction motifs. We hypothesize that these KSHV viral factors can bind to FHA proteins to alter their cellular functions to promote lytic cycle. To test this concept, here we aim to dissect the mechanism of one of these novel viral-FHA protein pairs and determine its role in the regulation of KSHV lytic cycle. We will also evaluate how this finding can be used for an antiviral therapy against KSHV.

NSF Awards · FY 2025 · 2025-07

Our oceans play a vital role in everything from coastal safety and national security to the economy and public health. Yet, large parts of the ocean remain difficult to explore and monitor. This project is focused on developing smarter and more reliable tools to help us better understand and navigate these vast underwater environments. Using new advances in robotics and artificial intelligence, the research team is working to improve small, cost-effective underwater robots that can travel long distances and operate on their own, even in areas where GPS and human control are unavailable. These mobile sensor platforms will be able to collect valuable information about the ocean in real time, adapt to changing conditions, and work together as a team — all without needing constant guidance. The project not only advances technology but also plays an important role in educating the next generation of scientists and engineers. The ability to monitor and survey oceans persistently and cost effectively on a large scale is of great significance to coastal safety, homeland security, national economy and public health. The proposed research addresses critical issues in transforming modern computing technologies for solving pressing problems of marine science. Recent decades marked a phenomenal transformation in our ocean exploration and perception approaches due to the progress in robotic computing platforms such as autonomous underwater vehicles (AUV). This research aims at enhancing the resilience and versatility of cyber-physical systems (CPS), consisting of mobile sensor platforms and ocean dynamics simulation, as our gateway to better explore and understand the harsh underwater environments. This project proposes research that will improve the long-term autonomy and intelligence of cost-effective mobile robots in previously under-explored ocean regions. Using Artificial Intelligence (AI) and Machine Learning (ML) techniques will enable mobile sensor networks with intelligent distributed sensing capabilities while ensuring their scalability and survivability within highly unpredictable dynamical environments. The developed strategies allow AUVs to localize themselves much more accurately in the oceans when GPS is not available. This project will also have a direct aim at training the next generation of engineers and computers scientists with expertise in naval architecture and marine sciences. In addition to the technical advances in CPS and AI used for ocean sampling, distributed sensing, and networking anticipated above, this project provides an application focus that will be of interest to researchers and students working in electrical, mechanical, and naval engineering, as well as computer, ocean, and biological sciences. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-07

Modern microelectronic computer chips include considerable low-level software critical to the system functionality. This software must be ready when the system is shipped to customers, and it is difficult to modify post deployment. One approach to ensure that the low-level software works as intended on the hardware is to produce a pre-production version of the chip for software/hardware testing, in a method referred to as "post-silicon validation". Post-silicon software validation is a highly complex and expensive activity requiring significant upfront planning and accounting for significant validation cost. Unfortunately, there has been little research in post-silicon software validation; existing research focuses primarily on functional and security validation of the underlying hardware. The project addresses this crucial problem via a comprehensive foundational paradigm and tool suite to streamline post-silicon software validation. The project’s key novelties include a unique architecture for observing hardware-software interaction in a silicon platform, methods to generate appropriate test inputs for exercising these interactions, and an objective metric to identify the quality of validation. The project’s broader impacts and significance include a pathway to derive high assurance in correctness of modern microelectronics systems that include tightly interacting hardware and software components, as well as creation of hands-on training modules to enable awareness in the problem for undergraduate and high-school students. The technical insight of the project is that a comprehensive post-silicon validation methodology requires cooperation of three components: an architecture for recording and transporting system events providing observability of the system internals during execution, a test generation methodology that is observability-aware, and a new coverage metric that accounts for the test scenarios being exercised and events being observed. The project realizes this insight through cooperative application of a novel architecture for collecting and synchronizing hardware-software events and a design automation flow that integrates this architecture with test generation and coverage calculation. The methodology targets validation of open-source System-on-Chip designs as well as emergent commercial systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT Supragingival dental plaque represents a degradative microbial community capable of fermenting a wide variety of sugars over a wide range of concentrations while adapting to the constant changes in carbohydrate source and availability in the oral cavity. Dental caries is developed due to a loss of balance between these fermentative activities, which release corrosive organic acids, and the activities of the host and microorganisms to neutralize acidic pH, resulting in a microbiome particularly good at producing and tolerating these acids. This biochemical imbalance is frequently accompanied by a microbial dysbiosis, where the biofilm is predominated by certain acid-producing and acid-tolerant species. Previous iterations of DE012236 established the foundation for the present work by focusing on the integration of carbohydrate metabolism and virulence development in the major caries etiological agent, Streptococcus mutans, in contrast to related commensal streptococci such as Streptococcus sanguinis and Streptococcus gordonii. Further, by studying a spectrum of sugar catabolism pathways, it was discovered that the mechanisms regulating sugar utilization in S. mutans, e.g., carbohydrate catabolite repression (CCR), cheating and bet-hedging behavior, deviate substantially from those of paradigm organisms. We posit that the deviation of S. mutans from these paradigms was driven by evolutionary adaptations that have imparted to this organism the necessary degree of flexibility to respond to the wide fluctuations in the amount and type of carbohydrates introduced into the human oral cavity. The present proposal builds on these previous studies and our recent discoveries in fructose metabolism and fructose-mediated cariogenicity and stress response, demonstrating the unique fitness of S. mutans that has evolved to better utilize this ubiquitous carbohydrate to enhance its competitiveness against the commensals. These fructose-specific phenotypes were further substantiated by the ability of fructose to activate in S. mutans the core functions of stress response and as many as 176 gene shared with a toxic glycolytic byproduct, methylglyoxal, including an uncharacterized conserved protein (GloA2) closely related to the enzyme required for degradation of methylglyoxal. There's now a large body of high-quality research evidence associating fructose with the ongoing epidemic of metabolic disorders: obesity, type 2 diabetes, cardiovascular diseases, and liver pathologies. As the component of two most widely used dietary sweeteners, sucrose and high- fructose corn syrup, fructose is likely contributing to the prevalence of caries among the western populations. To understand the molecular basis for, and ecological consequences of, fructose metabolism in dental biofilms, we present three Specific Aims: 1) In vitro characterization of the effects of fructose on streptococcal stress physiology; 2) Identifying genetic mechanisms required for fructose and GloA2-mediated response in S. mutans; 3) Assessing the contributions of fructose to microbial ecology and dysbiosis in biofilm models.